Clinical and Interpretive

Measurement of cortisol is useful in the discrimination between primary and secondary adrenal insufficiency and in the differential diagnosis of Cushing syndrome.

Cortisol, the main glucocorticoid (representing 75%-90% of the plasma corticoids) plays a central role in glucose metabolism and in the body’s response to stress.

Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (6 a.m.-8 a.m.) and nadirs (11 p.m.) in plasma ACTH and cortisol levels.

The majority of cortisol circulates bound to cortisol-binding globulin (CBG-transcortin) and albumin. Normally, <5% of circulating cortisol is free (unbound). The “free” cortisol is the physiologically active form. Free cortisol is filterable by the renal glomerulus.

Although hypercortisolism is uncommon, the signs and symptoms are common (eg, obesity, high blood pressure, increased blood glucose concentration). The most common cause of increased plasma cortisol levels in women is a high circulating concentration of estrogen (eg, estrogen therapy, pregnancy) resulting in increased concentration of cortisol-binding globulin.

Spontaneous Cushing syndrome results from overproduction of glucocorticoids as a result of either primary adrenal disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the most frequently diagnosed subtype; most commonly seen in women in the third through the fifth decades of life. The onset is insidious and usually occurs 2 to 5 years before a clinical diagnosis is made.

Causes of hypocortisolism are:
-Addison disease
-primary adrenal insufficiency
-Secondary adrenal insufficiency:
-Pituitary insufficiency
-Hypothalamic insufficiency
-Congenital adrenal hyperplasia
-defects in enzymes involved in cortisol synthesis

In primary adrenal insufficiency, adrenocorticotropic hormone (ACTH) levels are increased and cortisol levels are decreased; in secondary adrenal insufficiency, both ACTH and cortisol levels are decreased.

When symptoms of glucocorticoid deficiency are present and the 8 a.m. plasma cortisol value is <10 mcg/dL (or the 24-hour urinary free cortisol value is <50 mcg/24 hours), further studies are needed to establish the diagnosis. First, the basal plasma ACTH concentration should be measured, followed by the short cosyntropin stimulation test. Other frequently used tests are the metyrapone, and insulin-induced hypoglycemia test.

Cushing syndrome is characterized by increased serum cortisol levels. However, the 24-hour urinary free cortisol excretion is the preferred screening test for Cushing syndrome. A normal result makes the diagnosis unlikely.

Acute stress (including hospitalization and surgery), alcoholism, depression, and many drugs (eg, exogenous cortisones, anti-convulsants) can obliterate normal diurnal variation, affect response to suppression/stimulation tests, and cause elevated baseline levels.

Patients taking prednisone may have falsely increased cortisol levels because prednisone is converted to prednisolone after ingestion and prednisolone has a 41% cross-reactivity.

Cortisol levels may be increased in pregnancy and with exogenous estrogens.

Some patients with depressive disorders have a hyperactive hypothalamic-pituitary-adrenal axis, similar to Cushing syndrome.

NOT RECOMMENDED for evaluating response to metyrapone; DOC / 11-Deoxycortisol, Serum is more reliable.

A low plasma cortisol level does not give conclusive indication of congenital adrenal hyperplasia. DOC / 11 Deoxycortisol, Serum; OHPG / 17-Hydroxyprogesterone, Serum; and DHEA_ / Dehydroepiandrosterone (DHEA), Serum provide a better, accurate, and specific determination of the enzyme deficiency.